Neurobiology of chronic mild stress: parallels to major depression.

The chronic mild (or unpredictable/variable) stress (CMS) model was developed as an animal model of depression more than 20 years ago. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that was akin to the anhedonia observed in major depressive disorder. In the time since its inception, this model has also been used for a variety of studies examining neurobiological variables that are associated with depression, despite the fact that this model has never been critically examined to validate that the neurobiological changes induced by CMS are parallel to those documented in depressive disorder. The aim of the current review is to summarize the current state of knowledge regarding the effects of chronic mild stress on neurobiological variables, such as neurochemistry, neurochemical receptor expression and functionality, neurotrophin expression and cellular plasticity. These findings are then compared to those of clinical research examining common variables in populations with depressive disorders to determine if the changes observed following chronic mild stress are in fact consistent with those observed in major depression. We conclude that the chronic mild stress paradigm: (1) evokes an array of neurobiological changes that mirror those seen in depressive disorders and (2) may be a suitable tool to investigate novel systems that could be disturbed in depression, and thus aid in the development of novel targets for the treatment of depression.

Comparison of on-reserve road versus off-reserve road motor vehicle crashes in Saskatchewan, Canada: a case control study.

BACKGROUND: There is an overwhelmingly high incidence of severe injuries caused by motor vehicle crashes (MVCs) among Aboriginal Canadians as compared with the general population. METHODS: The authors obtained MVC data for a 3-year period, 2003-2005, from Saskatchewan Government Insurance (SGI) for collisions occurring on on-reserve roads (n = 1270) together with a randomly selected sample of MVCs from off-reserve roads (n = 1270) in Saskatchewan. They compared the collision characteristics using bivariate and multiple logistic regressions. RESULTS: On-reserve MVCs were more likely to include multiple collisions and result in severe injuries than the off-reserve sample. A number of factors were significantly related to the increased risk of on-reserve collisions as compared with the reference group for each variable. INTERPRETATION: Factors from all 3 levels (human, environmental, and vehicle factors) are associated with on-reserve MVCs.

Prenatal alcohol exposure and chronic mild stress differentially alter depressive- and anxiety-like behaviors in male and female offspring.

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neurobehavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals. METHODS: Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitum-fed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and/or anxiety-like behaviors. RESULTS: We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of "behavioral despair" in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females. CONCLUSIONS: These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations.

Circadian phase and sex effects on depressive/anxiety-like behaviors and HPA axis responses to acute stress.

Circadian dysregulation in sleep pattern, mood, and hypothalamic-pituitary-adrenal (HPA) axis activity, often occurring in a sexually dimorphic manner, are characteristics of depression. However, the inter-relationships among circadian phase, HPA function, and depressive-like behaviors are not well understood. We investigated behavioral and neuroendocrine correlates of depressive/anxiety-like responses during diurnal ('light') and nocturnal ('dark') phases of the circadian rhythm in the open field (OF), elevated plus maze (EPM), forced swim (FST), and sucrose contrast (SC) tests. Plasma corticosterone (CORT) was measured after a) acute restraint and OF testing and b) FST. Both phase and sex significantly influenced behavioral responses to stress. Males were more anxious than females on the EPM in the light but not the dark phase. Further, the open:closed arm ratio was lower in the dark for females, but not males. By contrast, in the FST, females showed more "despair" (immobility) when tested in the dark, while phase did not affect males. Acute restraint stress increased OF activity in the light, but not the dark, phase. CORT levels were increased in both sexes following the FST, and in males and light phase females post-OF. As expected, females had higher CORT levels than males, even at rest, and this effect was more pronounced in the dark phase. Together, our data highlight the sexually dimorphic influences of circadian phase and stress on behavioral and hormonal responsiveness.

Prenatal alcohol exposure: fetal programming and later life vulnerability to stress, depression and anxiety disorders.

Children with fetal alcohol spectrum disorder (FASD) exhibit cognitive, neuropsychological and behavioral problems, and numerous secondary disabilities including depression and anxiety disorders. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is common in depression/anxiety, reflected primarily in increased HPA tone or activity. Prenatal alcohol exposure (PAE) increases HPA tone and results in HPA dysregulation throughout life, paralleling many of the HPA changes in depression/anxiety. We review data demonstrating altered HPA function and increased depression/anxiety in FASD. In the context of the stress-diathesis model, we discuss the hypothesis that fetal programming of the HPA axis by PAE alters neuroadaptive mechanisms that mediate the stress response, thus sensitizing the organism to stressors encountered later in life, and mediating, at least partly, the increased vulnerability to depression/anxiety disorders. Furthermore, we present evidence demonstrating sex-specific alterations in both hormonal and behavioral responsiveness to tasks measuring depressive- and anxiety-like behaviors in PAE offspring. Overall, the research suggests that the stress-diathesis model provides a powerful approach for elucidating mechanisms underlying the increased vulnerability to mental illness among individuals with FASD, and developing appropriate treatments for these individuals. Dr. Seymour Levine's seminal work on the long-term consequences of early life experiences formed a framework for the development of the research described in this review.

Prenatal alcohol exposure increases vulnerability to stress and anxiety-like disorders in adulthood.

Children and adults with fetal alcohol spectrum disorder (FASD) have elevated rates of depression and anxiety disorders compared to control populations. The effects of prenatal alcohol exposure (PAE) on anxiety, locomotor activity, and hormonal reactivity in male and female rats tested on the elevated plus maze (EPM), a task commonly used to assess anxiety-like behaviors in rodents, were examined. Pregnant dams were assigned to PAE, pair-fed (PF), or ad libitum-fed control (C) groups. At adulthood, half of all male (N= 60) and female (N= 60) PAE, PF, and C offspring were exposed to 10 days of chronic mild stress (CMS); the other half remained undisturbed. Animals were then tested on the EPM, and blood collected 30 min posttest for analysis of corticosterone (CORT), testosterone, estradiol, and progesterone. Overall, CMS exposure produced a significant anxiogenic profile. Moreover, CMS increased anxiety-like behavior in PAE males and females compared to controls and eliminated the locomotor hyperactivity observed in nonstressed PAE females. CMS also increased post-EPM CORT, testosterone, and progesterone levels in all groups, with CORT and progesterone levels significantly higher in PAE than in C females. By contrast, CMS selectively lowered estradiol levels in PAE and PF, but not C, females. CMS exposure reveals sexually dimorphic behavioral and endocrine alterations in PAE compared to C animals. Together, these data suggest the possibility that fetal reprogramming of hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) systems by alcohol may underlie, at least partly, an enhanced susceptibility of fetal alcohol-exposed offspring to depression/anxiety-like disorders in adulthood.